Losartan potassium Hydrochlorothiazide Combizar® 50 mg/12.5 mg, 100 mg /25 mg Tablet Angiotensin II Receptor Antagonist / Diuretic / Antihypertensive FORMULATION Each tablet contains: Losartan potassium ........sssssssssstenesisssssssesseesensnenees ... 50 mg Hydrochlorothiazide. 12.5mg or Losartan potassium ........ssscsssscssnenesiessssstssesssssemescessseneeeseessenees 100 MQ Hydrochlorothiazide. 25mg RATIONALE OF THE COMBINATION Losartan and hydrochlorothiazide (HCTZ) are used together in a once daily oral fixed- dose combination (FDC) to manage hypertension. Losartan is a specific and selective angiotensin || receptor antagonist while HCTZ is a thiazide diuretic. The effects of both drugs on blood pressure are additive. Greater antihypertensive efficacy is generally achieved by adding a small dose of a thiazide diuretic such as HCTZ to the angiotensin- Il receptor antagonist. Losartan lowers blood pressure by selectively blocking the AT4 receptor in vascular and other tissues to antagonize the actions of angiotensin Il. HCTZ, on the other hand, lowers blood pressure by increasing the renal excretion of sodium: Losartan tends to reverse hypokalemia caused by HCTZ. PHARMACOLOGIC ACTIONS Losartan potassium Angiotensin Il is a potent vasoconstrictor, the primary vasoactive hormone of the renin- angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin || to the AT receptor found in many tissues. There is also an AT? receptor found in many tissues but is not known to be associated with cardiovascular homeostasis. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non- competitive inhibitor of the AT receptor. Neither losartan nor its active metabolite inhibits ACE, nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Hydrochlorothiazide (HCTZ) Hydrochlorothiazide is a thiazide diuretic. Thiazides increase the excretion of water by inhibiting the reabsorption of sodium and chloride ions at the distal renal tubule. The natriuretic effects are accompanied by a secondary loss of potassium and bicarbonate which can cause a mild hypokalemic, hypochloremic, metabolic alkalosis. Thiazides also decrease the elimination of calcium and uric acid. Thiazide diuretics usually do not affect normal blood pressure. When chronically administered, thiazide diuretics decrease peripheral vascular resistance. The exact mechanism responsible for lowered peripheral resistance is not known, however, excretion of urinary sodium by the kidneys is required to achieve blood pressure reduction. Initially, diuretics lower blood pressure by decreasing cardiac output, plasma volume and extracellular fluid volume. Cardiac output eventually returns to normal, plasma and extracellular fluid values return slightly less than normal, but peripheral vascular resistance is reduced, resulting in lower blood pressure. PHARMACOKINETICS The combination of losartan and hydrochlorothiazide (HCTZ) is administered orally. The blood pressure lowering effect of losartan is additive with that of HCTZ. Losartan potassium Following oral administration, losartan is well absorbed but undergoes presystemic metabolism, forming an active metabolite (E-3174) and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations: of losartan and its active metabolites are reached in 1 hour and in 3-4 hours, respectively. There is no clinically significant effect on the plasma concentration profile of losartan when the drug is administered with a meal. Both losartan and its metabolite are 2 99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is relatively low at 34 liters. Plasma concentrations of the active metabolite are higher than those of losartan at all doses, Cmax and AUC for E-3174 are approximately 2 and 5-8 times greater than the corresponding values for losartan itself. Following oral administration, the plasma concentration of losartan, and its active metabolite, decline polyexponentially, with terminal half-lives of about 2 hours (1.5-2.5 hours) and 6-9 hours, respectively. As anticipated from their short half-lives, neither losartan nor its active metabolite accumulates significantly in plasma during once daily dosing with 100 mg. The plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Losartan is extensively metabolized in the liver. Approximately 35% of an oral dose is excreted in the urine as unchanged compound and metabolites. Only 4% of the dose is eliminated unchanged via the kidneys. The renal clearance of losartan is 74 mL/min. Approximately 6% of the dose is excreted in urine as the active metabolite with a renal clearance of 26 mL/min. Losartan and its metabolites are also eliminated by biliary excretion, with 58% of an oral dose recovered in the feces Hydrochlorothiazide (HCTZ) Hydrochlorothiazide is variably absorbed from the gastrointestinal tract depending on the formulation and dose. The systemic bioavailability is approximately 50-60%. After oral administration of HCTZ, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. The duration of action ranges from 6-12 hours. The drug crosses the placenta, but not the blood-brain barrier and is distributed in breast milk. HCTZ is not metabolised but is eliminated unchanged within 24 hours. The elimination half-life of HCTZ was originally reported to range from 5.6-14.8 hours when plasma levels were followed for at least 24 hours. A more recent study reports a mean elimination half- life of 2.5 hours in patients with normal renal function. The elimination half-life is estimated to increase 12-20 hours in patients with severe renal disease (e.g. creatinine clearance < 10 mL/min). ADVERSE EFFECTS In general, treatment with losartan potassium-hydrochlorothiazide was well tolerated. For the most part, adverse experiences have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in only 2.8% and 2.3% of patients treated with the combination and placebo, respectively. The following adverse experiences were reported with losartan-hydrochlorothiazide: Body as a Whole: Abdominal pain, edema/swelling, asthenia/fatigue, headache Cardiovascular: Palpitation Gastrointestinal: Diarrhea, nausea Musculoskeletal: Back pain Nervous/Psychiatric: Dizziness Respiratory: Dry cough, sinusitis, bronchitis, pharyngitis, upper respiratory infection Skin: Rash DRUG INTERACTIONS Losartan potassium When given concurrently, the following drugs may interact with losartan: Cimetidine — Increase of about 18% in AUC of losartan may occur but with no effect on the pharmacokinetics of its active metabolite. Phenobarbital — Reduction of about 20% in the AUC of losartan and that of its active metabolite. Rifampicin and fluconazole — Reduction in levels of losartan’s active metabolite. Potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium — Increases in serum potassium Hydrochlorothiazide (HCTZ) When given concurrently, the following drugs may interact with HCTZ: Alcohol, barbiturates, or narcotics — Potentiation of orthostatic hypotension may occur. Antidiabetic drugs (oral agents and insulin) — Dosage adjustment of the antidiabetic drug may be required. Cholestyramine and colestipol resins — Absorption of HCTZ is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the HCTZ and reduce its absorption from the gastrointestinal tract by up to 85 and 43%, respectively Corticosteroids, ACTH — Intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., adrenaline) - Possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) — Possible increased responsiveness to the muscle relaxant. Lithium — Diuretics reduce the renal clearance of lithium and add a high risk of lithium toxicity. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) — NSAIDs can reduce the diuretic, natriuretic, and antihypertensive effects of HCTZ. INDICATION Treatment of hypertension; for patients in whom combination therapy is appropriate DOSAGE AND ADMINISTRATION Usual Initial & Maintenance Adult Dose: 1 tablet of Losartan 50mg + HCTZ 12.5mg FDC once daily. + For patients who do not respond adequately, adjust to a maximum dose of: 1 tablet of Losartan 100 mg + HCTZ 25 mg FDC daily or, 2 tablets of Losartan 50 mg + HCTZ 12.5 mg FDC daily + In general, the antihypertensive effect is attained within 3 weeks after initiation of therapy. Or as prescribed by the physician CONTRAINDICATIONS + Hypersensitivity to any component of the product + Hypersensitivity to suifonamide-derived drugs + Pregnancy + Patients with anuria WARNINGS USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act on the renin-angiotensin system (e.g., losartan) can cause injury and even death to the developing fetus. When pregnancy is detected, discontinue losartan as soon as possible. PRECAUTIONS + Do not initiate use of losartan-HCTZ FDC in patients who are intravascularly volume- depleted (e.g., those treated with high-dose diuretics) + Losartan-HCTZ FDC is not recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min) or patients with hepatic impairment + Based on pharmacokinetic data demonstrating significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment. Hence, losartan-HCTZ FDC is not recommended for patients who require dose titration with losartan + Losartan may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. These changes in renal function may be reversible upon discontinuation of therapy. + Use in Nursing Women: It is not known whether losartan is excreted in human milk. HCTZ appears in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. CAUTION Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription. STORE AT TEMPERATURES NOT EXCEEDING 30°C Availability: Combizar® 50mg/12.5mg Tablet, in blister pack x 10's (Box of 50's) Combizar® 100mg/25mg Tablet, in blister pack x 10's (Box of 50's) Date of Last Revision: May 2012 Manufactured by Amherst Laboratories, Inc. UNILAB Pharma Campus, Brgy. Mampiasan Bifian, Laguna, Philippines Distributed by United Laboratories, Inc. 66 United Street, Mandaluyong City, Philippines Under authority by THERAPHARMA, INC. 3/F Bonaventure Plaza, Ortigas Avenue ‘ Greenhills, San Juan City, Philippines Trusted Quality Health: P30000008513 Reg IPOPHIL